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. 2022 Aug 12;12:927193. doi: 10.3389/fcimb.2022.927193

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Copyright © 2022 Zhou, Jin, Pan, Lin, Yang, Ambe, Basharat, Zimmer, Wang and Hong

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Extracellular CIRP (eCIRP) is released to the extracellular space via necrosis or lysozyme extracellular pathway, afterward binds to the TLR4-MD2 receptor complex on macrophages, activates the TLR4/MyD88/NF-κB pathway and induces macrophages to release pro-inflammatory cytokines (TNF-A, IL-6, Il-1b), chemokines (keratinocyte chemical attractor and MIP-2), and HMGB1. This pathway also promotes mitochondrial DNA damage and degradation, leading to STING activation, which leads to the production of type I IFN and pro-inflammatory cytokines.